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"Sympathetic overactivity: A risk factor in cardiovascular
disease"
Professor Henry Krum
Director, NHMRC Centre of Clinical Research Excellence in Therapeutics,
Monash University/Alfred Hospital, Melbourne, Australia
Sympathetic overactivity is a major etiological and adverse prognostic factor in many
cardiovascular disease states, including systemic hypertension, atherosclerosis and
chronic heart failure.
Clustering of the risk factors of hypertension, impaired glucose tolerance and
hyperlipidemia form the tenets of the metabolic syndrome. Sympathetic hyperactivity
is an important component of this syndrome, in association with insulin resistance.
Sympathetic overactivity in this setting contributes to concomitant diseases as diverse
as atherosclerosis, left ventricular hypertrophy and a pro-coagulant state.
In chronic heart failure there is marked activation of the sympathetic nervous system,
particularly organ-specific within the heart and kidney. There is also withdrawal of
parasympathetic activity. Both of these disorders of autonomic regulation have been
found to have independent adverse prognostic significance.
Blockade of sympathetic activity has represented a major advance in the treatment of
chronic heart failure. This has been achieved most prominently with beta-adrenoceptor
blocking agents, although central sympatho-inhibition and blockade of catecholamine
synthesis has also been actively explored, albeit with less success.
There is considerable interaction between the sympathetic nervous system (SNS) and
the renin-angiotensin-aldosterone system (RAAS). Interactions between the RAAS and
SNS may potentially occur at a number of sites. These include central sites (eg, rostral
ventrolateral medulla), at the level of baroreflex control, and at the sympathetic
prejunctional angiotensin II (AII) receptor I (AT 1) receptor, which is facilitatory for
norepinephrine release from the sympathetic nerve terminal. Therefore, drugs that
block the RAAS may be expected to improve autonomic dysfunction in cardiovascular
disease states.
In order to test the hypothesis that RAAS inhibition directly reduces SNS activity, a
pithed rat model of sympathetic stimulation has been established. In this model, an
increase in frequency of stimulation results in a pressor response that is
sympathetically-mediated and highly reproducible. This pressor response is enhanced in
the presence of angiotensin II and is reduced in the presence of non-selective AII
receptor antagonists that block both AT1 and AT2 receptor subtypes (eg saralasin).
AT1-selective antagonists have also been studied in this model, at pharmacologically
relevant doses.
The AT1 blocker eprosartan reduced sympathetically-stimulated
increases in blood pressure to a greater extent than comparable doses of losartan,
valsartan, and irbesartan.
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Reason(s) for the apparent differences between eprosartan and other agents of this
class on sympathetic modulation are not clear, but may relate to the chemical structure
of the drug (a non-biphenyl tetrazole structure that is chemically distinct from the
structure of other AIIRAs), receptor binding characteristics (competitive), or unique
effects on presynaptic AT1 receptors.
Clinical trials directly comparing the autonomic effects of AT 1-selective antagonists
have been completed, testing the hypotheses raised regarding these agents in the above
animal studies. These data should help clarify the true clinical role of these agents in
modulating not just the RAAS but also the SNS in relevant disease states.
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